The invention concerns immunodeficient conditions which are caused by or which involve dysfunction of the cell-mediated immune system and which may be reflected by infection with and disease caused by other pathogenic microorganisms which may be viral, bacterial, fungal or protozoal in nature. For example, candidiasis and histoplasmosis are caused by fungal organisms, tuberculosis is caused by a bacterium, and shingles is caused by the re-emergence of Herpes zoster in adults who have previously had chicken pox, the primary manifestation of infection with this virus in childhood.
A typical manifestation of cell-mediated immunity is the delayed type hypersensitivity (“DH”) skin reaction. A DH skin reaction is observed when an appropriate antigen is injected intradermally. Within 24 to 48 hours, local inflammation (erythema) and a swelling and thickening (induration) are observed in a sensitive individual. The degree of sensitivity may be measured by the size and severity of the reaction. The DH reaction also presents characteristic histological findings—specifically, perivascular infiltration of leukocytes and monocytes in the inflamed area. The cells seen at the site of a DH reaction are derived from the peripheral blood leukocyte population.
The mechanisms of cell-mediated immunity are as yet incompletely understood. It is known that the cells which mediate the response are capable of responding in a variety of ways to a challenge from an antigen. These responses include: proliferation of cells bearing specific sensitivity to a given antigen; the induction and multiplication of cells mediating a variety of immune functions, including antibody production; and reactions against foreign cells and tumors.
Gottlieb U.S. Pat. No. 4,468,379 disclosed that endogenous materials isolated from human leukocyte dialysates exist that amplify the speed and magnitude of cell-mediated immune system response. These immunoamplifier materials are distinguished from so-called transfer factors in that immunoamplifiers do not transfer to a subject an immune response to a mitogen or antigen to which the subject has not previously been exposed and is not concurrently exposed, while transfer factors are said to do so. Moreover, immunoamplifiers nonspecifically increase cell-mediated immune system responses to mitogens and antigens to which the subject has previously been or concurrently is exposed, while transfer factors are specific to particular antigens.
The material designated “amplifier 1” in the '379 patent was subsequently determined to be a mixture of various things. They include (1) what is referred to subsequently in Gottlieb U.S. Pat. No. 5,081,108 and Gottlieb U.S. Pat. No. 5,100,663 as YG Product, (2) what is referred to in Gottlieb U.S. Pat. No. 5,081,108 as YGG Product, (3) another as-yet undefined or incompletely defined amplifier, (4)=various amino acid products, and (5) other materials. The foregoing materials occurred in amplifier 1 in varying relative proportions, depending on the identity of the blood sample from which the sample of amplifier 1 was derived. Such variation appears to reflect the fact that the content of a human blood sample varies from donor to donor and even for the same donor from time to time, depending on the state of the immune system of the donor. The fact that the content of amplifier 1 varied from sample to sample adversely affected the repeatability of experiments directed toward establishing the immunologic activity of amplifier 1. That in turn adversely affected ability to establish product identity, standard dosages, assays, and the like for amplifier 1. These factors have hindered therapeutic utilization of products based on amplifier 1.
Gottlieb U.S. Pat. No. 4,616,079 suggested that amplifiers may act on T-helper cells (T4 cells) in a way that causes them to produce chemical mediators (cytokines) whose effect is to increase the speed and/or magnitude of cell-mediated immune system response to antigens and other means of activating a cell-mediated immune system response. Indicia of this response include DH reaction to recall antigens, production of IL-2 and gamma interferon, and potentiation of cytotoxic cells.
Gottlieb U.S. Pat. No. 4,699,898 and Gottlieb U.S. Pat. No. 5,100,068 disclosed that Tyr-Gly and Tyr-Gly-Gly peptides are immunologically active components in the partially purified dialysate fractions previously described in earlier Gottlieb patents, such as Gottlieb U.S. Pat. No. 4,616,079. The ability of YG Product and YGG Product to affect immune responses has been confirmed in subsequent literature. See, e.g., B. Zacharie et al., Thioamides: Synthesis, stability, and immunologic activities of thioanalogues of Imreg, Preparation of new thioacylating agents using fluorobenzimidazolone derivatives, 42 J. MED. CHEM. 2046 (1999).
Finally, it may be helpful to refer for background purposes to A. Gottlieb et al., Decrease in serum HIV RNA following treatment with a leukocyte dialysate fraction (LDS) that contains N-terminal peptides of the enkephalins and enhances cell-mediated immunity, in INTERNATIONAL CONGRESS OF IMMUNOLOGY, NEW DELHI, INDIA 883-99 (G. P. Talwar et al. eds. 1998)(pub. Monduzzi Editore SpA, Bologna, Italy).
It is known that various diseases and pathological conditions, such as HIV Disease and AIDS, as well as chemotherapy, radiation, and aging, depress the immune system response. A result is increased susceptibility to opportunistic infections, malignancies, and other pathological conditions that a normal immune system would have confronted. Frequently (and for some conditions, invariably), the result is death.
It is now believed that amount of viral load is related to the severity of HIV Disease and AIDS symptoms. By the same token, therapies have been sought that would decrease viral load. As yet, many such therapies have undesirable side effects and/or their effectiveness diminishes after use for a time. It would be desirable to have a therapy for reduction of viral load that caused fewer or no side effects. It would also be desirable to have a therapy for reduction of viral load that did not diminish in effectiveness after use for a time.
It is known that a desired therapeutically active molecule may be delivered by administering to a patient a different molecule that hydrolyzes, as a result of the action of endogenous enzymes, to fractions that include the desired therapeutically active molecule. Hetacillin is a well known example. Hetacillin breaks down in the human body to ampicillin. A legal controversy ensued internationally, following the introduction of hetacillin, over whether the manufacture, use, and sale of hetacillin infringed patents on ampicillin.
It is known that desired therapeutically active molecules may be degraded by enzymatic hydrolysis, and that such process may sometimes be retarded or prevented by use of the principle of so-called steric hindrance. This term refers to placement of a radical such as methyl in a location where an enzyme might otherwise cause hydrolysis. This principle has been used, largely on a trial and error basis, to create synthetic penicillinase and other hydrolysis-resistant drugs. It is also known to N-methylate the Tyr residue of Tyr-Gly or Tyr-Gly-Gly to inhibit such enzymatic action. It is also known to esterify or amidify the C-terminal carboxyl group to inhibit enzymatic cleavage.
Tyr-Gly and Tyr-Gly-Gly have been sold as chemical reagents (L-tyrosyl-glycine and L-tyrosylglycylglycine) by Sigma Chemical Co., St. Louis, Mo., among others. Tyr-Gly and Tyr-Gly-Gly are not sold in U.S.P. grade, and it is illegal under applicable laws to sell Tyr-Gly or Tyr-Gly-Gly for use as a pharmaceutical. Commercial grade Tyr-Gly and Tyr-Gly-Gly are not considered free of pyrogens, endotoxin, and other pharmaceutically unacceptable constituents. The presence of such pyrogens, endotoxin, and other pharmaceutically unacceptable constituents makes a product unacceptable for use as a drug, as that term is defined by federal statute, both under generally recognized medical principles and under FDA regulations.
Over the years in the literature and in prior Gottlieb patents, the usage of the terms “amplifier”, “immunoamplifier”, “amplifier of the immune system”, and related terms may not have been uniform. It should be understood that “immunoamplifier” as used in this application means the same as those other terms in prior applications and publications.